Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis.

Scheving LA, Zhang X, Stevenson MC, Weintraub MA, Abbasi A, Clarke AM, Threadgill DW, Russell WE
Am J Physiol Gastrointest Liver Physiol. 2015 309 (12): G942-54

PMID: 26492920 · PMCID: PMC4683301 · DOI:10.1152/ajpgi.00089.2015

Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.

Copyright © 2015 the American Physiological Society.

MeSH Terms (19)

Age Factors Animals Cell Proliferation Cell Transformation, Neoplastic Diethylnitrosamine ErbB Receptors Genotype Hepatocytes Liver Neoplasms Liver Regeneration Male Mice, 129 Strain Mice, Inbred C3H Mice, Knockout Phenotype Phosphorylation Receptor, ErbB-3 Signal Transduction STAT3 Transcription Factor

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